5-(1-hydroxylcycloalkyl)-2-methoxy pyridine compounds

ABSTRACT

There are described compounds of the formula ##STR1## where n is 1, 2 or 3; 
     R 1  is hydrogen, formyl, loweralkylcarbonyl, arylloweralkylcarbonyl, loweralkyl, arylloweralkyl, ##STR2##  R 5  and R 6  being independently loweralkyl or alternatively the group ##STR3##  taken as a whole is ##STR4## R 2  is hydrogen, loweralkyl, loweralkenyl, arylloweralkyl, --CH 2  C.tbd.CH, ##STR5##  R 7  and R 8  being independently loweralkyl or alternatively the group ##STR6##  taken as a whole is ##STR7## R 3  is hydrogen is loweralkyl; and R 4  is hydrogen or loweralkyl; 
     which compounds are useful as analgesic agents and also for treating various memory dysfunctions.

This is a division of a prior application, Ser. No. 710,472, filed Jun.5, 1991, now U.S. Pat. No. 5,112,981, which is a division of a priorapplication, Ser. No. 594,496, filed Oct. 9, 1990, now U.S. Pat. No.5,039,809, which is a division of a prior application, Ser. No. 394,448,filed Aug. 16, 1989, now U.S. Pat. No. 4,978,663.

This invention relates to compounds having the formula ##STR8## where nis 1, 2 or 3;

R₁ is hydrogen, formyl, loweralkylcarbonyl, arylloweralkylcarbonyl,loweralkyl, arylloweralkyl, ##STR9## R₅ and R₆ being independentlyloweralkyl or alternatively the group ##STR10## taken as a whole is##STR11## R₂ is hydrogen, loweralkyl, loweralkenyl, arylloweralkyl,--CH₂ C.tbd.CH, ##STR12## R₇ and R₈ being independently loweralkyl oralternatively the group ##STR13## taken as a whole is ##STR14## R₃ ishydrogen or loweralkyl; and R₄ is hydrogen or loweralkyl;

which compounds are useful as analgesic agents and also for treatingvarious memory dysfunctions.

Also included within the scope of this invention are compounds ofFormulas II and III where R₉ is hydrogen, loweralkyl or arylloweralkylwhich compounds are useful as direct precursors of the target compoundsof this invention. ##STR15##

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, geometrical and opticalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following definitions shall apply throughout the specification andthe appended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkyl include methyl, ethyl, n-propyl, iso-butyl,pentyl and hexyl.

The term loweralkenyl shall mean a straight or branched alkenyl grouphaving from 1 to 6 carbon atoms and only one carbon-carbon double bond.Said double bond shall not be at the alpha-position with respect to theposition where the loweralkenyl substituent is located.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup optionally mono-substituted with a loweralkyl, loweralkoxy,halogen or trifluoromethyl group.

The compounds of this invention are prepared by utilizing one or more ofthe synthetic steps described below.

Throughout the description of the synthetic steps, the definitions of nand R₁ through R₉ are as given above unless otherwise stated orindicated, and other nomenclatures shall have their respective meaningsgiven in their first appearances.

STEP A

5-Bromo-2(1H)-pyridinone is allowed to react withtriisopropylsilyl-trifluoromethanesulfonate to afford5-bromo-2-(triisopropylsilyloxy)pyridine having the formula IV.##STR16##

The above reaction is typically conducted in the presence of a suitableacid scavenger such as 2,6-dimethylpyridine and a suitable solvent suchas dichloromethane at a temperature of about 0° to 25° C.

STEP B

Compound IV is allowed to react with n-BuLi and thereafter the resultantanion is allowed to react with a cyclic ketone of Formula V to afford acompound of Formula VI. ##STR17##

The reaction between compound IV and n-BuLi is typically conducted in asuitable solvent such as diethyl ether at a temperature of about -78° to0° C. The subsequent reaction between the resultant complex and compoundV is typically conducted in the same solvent at a temperature of about-78° to 25° C.

STEP C

Compound VI is allowed to react with hydrofluoric acid to afford acompound of Formula VII. ##STR18##

The above reaction is typically conducted by adding an aqueous solutionof HF to a solution of compound VI in a suitable solvent such asacetonitrile and stirring the resultant mixture at a temperature ofabout 0° to 25° C.

STEP D

Compound VII is allowed to react with a halide compound of the formulaR₁₀ -Hal, where Hal is chlorine, bromine, or iodine and R₁₀ isloweralkyl or arylloweralkyl, in a routine manner known to the art toafford a compound of Formula VIII. ##STR19##

As an alternative to the foregoing STEPS A through D, one can alsoutilize STEPS E and F described below.

STEP E

5-Bromo-2-methoxypyridine is allowed to react with n-BuLi and thereafterthe resultant anion is allowed to react with compound V in substantiallythe same manner as in STEP B to afford a compound of Formula IX.##STR20##

STEP F

Compound IX is allowed to react with a halide compound of the formulaR₁₀ -Hal where Hal is bromine or iodine to afford compound VIII.

    (IX)+R.sub.10 -Hal→(VIII)

The above reaction is typically conducted in the presence of aninorganic base such as potassium carbonate and a suitable medium such asacetonitrile at a temperature of about 60° to 85° C.

STEP G

A compound of Formula X which is obtained from STEP C, D or F is allowedto undergo Ritter reaction with HCN whereby the tertiary --OH group ofcompound X is converted to a --NHCHO group to afford a compound ofFormula XI. ##STR21##

Typically, the above reaction is conducted in the presence of potassiumcyanide, trifluoroacetic acid and concentrated sulfuric acid at atemperature of about 0° to 25° C.

STEP H

Compound X is allowed to undergo Ritter reaction with a nitrile compoundof the formula R₁₁ -CN where R₁₁ is loweralkyl to afford a compound ofFormula XII. ##STR22##

Typically, the above reaction is conducted in the presence ofconcentrated sulfuric acid. Optionally, the nitrile R₁₁ CN ortrifluoroacetic acid may be used as a cosolvent. Typically, the reactionis conducted at a temperature of about 0° to 25° C.

STEP I

Compound XI is reduced with NaBH₄ to afford a compound of Formula XIII.##STR23##

Typically, the above reaction is conducted in a suitable medium such asa mixture of acetic acid and tetrahydrofuran at a temperature of about50° to 65° C.

STEP J

Compound XI is hydrolyzed to afford a compound of Formula XIV. ##STR24##

The above reaction is typically conducted in the presence ofhydrochloric acid and methanol at a temperature of about 25° to 65° C.

STEP K

Compound XIV is allowed to react with an acid anhydride of the formula##STR25## where R₁₂ is loweralkyl or arylloweralkyl, or with an acidhalide of the formula ##STR26## where Hal is chlorine or bromine toafford a compound of Formula XV. ##STR27##

The above reaction is typically conducted in the presence of an acidscavenger such as triethylamine and a suitable solvent such asdichloromethane at a temperature of about 0° to 25° C.

STEP L

A compound of Formula XIVa obtained from STEP J is allowed to reactpreferably with about two molar equivalents of a compound of the formula##STR28## where Ar is an aryl group and Hal is chlorine or bromine, toafford a compound of Formula XVI. ##STR29##

The novel compounds of Formula XVI are within the scope of thisinvention.

STEP M

Compound XVI is hydrolyzed to afford a compound of Formula XVII.##STR30##

This hydrolysis is typically conducted with the aid of an acid and asolvent which are similar to those used in STEP J.

STEP N

Compound XIVa is allowed to react withtriisopropylsilyltrifluoromethanesulfonate in substantially the samemanner as in STEP A and thereafter the resultant product is allowed toreact with chloroacetic anhydride to afford a compound of Formula XVIII.##STR31##

The second reaction mentioned above is typically conducted in thepresence of poly(4-vinylpyridine) and a catalytic amount ofN,N-dimethyl-4-aminopyridine as well as a suitable solvent such asdichloromethane at a temperature of about 0° to 25° C.

STEP O

Compound XVIII is allowed to react with a tertiary amine of the formula##STR32## to afford a compound of Formula XIX. ##STR33##

The above reaction is typically conducted in the presence of a tertiaryamine such as diisopropylethylamine and a suitable solvent such asacetonitrile at a temperature of about 50° to 65° C.

STEP P

A compound of Formula XIa obtained from STEP G is allowed to react withBrCH₂ C.tbd.CSi(CH₃)₃ to afford a silyl compound of Formula XX. Thisreaction is typically conducted in the presence of an inorganic basesuch as K₂ CO₃ and a suitable solvent such as dimethylformamide at atemperature of about 25° to 50° C. ##STR34##

Subsequently, compound XX is allowed to react with tetra-n-butylammoniumfluoride to afford a compound of Formula XXI. This reactions istypically conducted in the presence of a suitable solvent such astetrahydrofuran at a temperature of about 0° to 25° C. ##STR35##

STEP Q

Compound XXI is allowed to react with paraformaldehyde and a secondaryamine of the formula ##STR36## to afford a compound of Formula XXII(Mannich reaction). This reaction is typically conducted in the presenceof cuprous chloride and a suitable solvent such as dioxane at atemperature of about 25° to 80° C. ##STR37##

STEP R

Compound XXII is hydrolyzed in substantially the same manner as in STEPJ to afford a compound of Formula XXIII. ##STR38##

STEP S

One of the primary amino hydrogens of compound XXIII can be converted tovarious other functional groups falling within the definition of R₁ byutilizing STEPS K, L, M, N and/or O described above. ##STR39##

STEP T

A compound of Formula XXV obtained by utilizing one or more of theforegoing steps is catalytically hydrogenated to afford a compound ofFormula XXVI. This hydrogenation is typically conducted with the aid ofa suitable catalyst such as Pd on BaSO₄ and a suitable medium such asmethanol at a temperature of about 25° to 50° C. ##STR40##

STEP U

Compound XXVI is catalytically hydrogenated to afford a compound ofFormula XXVII. This hydrogenation is typically conducted with the aid ofa suitable catalyst such as Pd on carbon and a suitable medium such asethanol at a temperature of about 25° to 40° C. ##STR41##

The compounds of Formula I of the present invention are useful asanalgesic agents due to their ability to alleviate pain in mammals. Theactivity of the compound is demonstrated in the2-phenyl-1,4-benzoquinone-induced writhing test in mice, a standardassay for analgesia [Proc. Soc. Exptl. Biol. Med., 95,729 (1957)]. Table1 shows results of the test for of some of the compounds of thisinvention.

                  TABLE 1                                                         ______________________________________                                        ANALGESIC ACTIVITY                                                            (Phenylquinone Writhing)                                                                   Analgesic PQW,                                                                % Inhibition of                                                               Writhing at                                                      Compound     20 mg/kg., s.c.                                                  ______________________________________                                        cis-N-[1-(1,6-Dihydro-1-                                                                            47%                                                     methyl-6-oxo-3-pyridinyl)-                                                    4-(1,1-dimethylethyl)cyclohexyl]                                              acetamide                                                                     5-(1-Amino-4,4        62%                                                     dimethylcyclohexyl)-2(1H)-                                                    pyridinone hydrochloride                                                      5-(1-Aminocyclohexyl)-                                                                              42%                                                     1-(phenylmethyl)-2(1H)-pyridinone                                             hydrochloride                                                                 N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)-                                                               77%                                                     cyclohexyl][4-(4-fluorobenzoyl)]-                                             1-piperidineacetamide                                                         N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)-                                                               58%                                                     cyclohexyl]acetamide                                                          N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)-                                                               72%                                                     cyclohexyl]benzamide                                                          5-(1-Aminocyclohexyl)-1-[4-(pyrrolidin-                                                             53%                                                     1-yl)-2-butynyl]-2(1H)-pyridinone                                             (Reference Compound)                                                          Propoxyphene          50% at 3.9 mg/kg, s.c.                                  ______________________________________                                    

The compounds of Formula (I) of the present invention can also be usedfor the treatment of various memory dysfunctions such as Alzheimer'sdisease.

This utility can be ascertained by determining the ability of thesecompounds to restore cholinergically deficient memory in the DarkAvoidance Assay. In this assay mice are tested for their ability toremember an unpleasant stimulus for a period of 24 hours. A mouse isplaced in a chamber that contains a dark compartment; a strongincadescent light drives it to the dark compartment, where an electricshock is administered through metal plates on the floor. The animal isremoved from the testing apparatus and tested again, 24 hours later, forthe ability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment. Results of Dark AvoidanceAssay for representative compounds of this invention and a referencecompound are presented in Table 3.

                  TABLE 2                                                         ______________________________________                                        Dark Avoidance Assay                                                                                     % of animals with                                                             scopolamine induced                                                 Dose      memory deficit                                     Compound         mg/kg, s.c.                                                                             reversal                                           ______________________________________                                        5-(1-Aminocyclohexyl)-                                                                         0.16      20%                                                1-(phenylmethyl)-2(1H)-                                                       pyridinone hydrochloride                                                      5-(1-Amino-4,4-  2.5       20%                                                dimethylcyclohexyl)-2(1H)-                                                    pyridinone hydrochloride                                                      cis-N-[1-(1,6-Dihydro-1-                                                                       1.3       33%                                                methyl-6-oxo-3-pyridinyl)-                                                    4-(1,1-dimethylethyl)                                                         cyclohexyl]-acetamide                                                         N-[1-(1,2-Dihydro-1-methyl-                                                                    0.63      33%                                                2-oxo-5-pyridinyl)cyclohexyl]-                                                acetamide                                                                     Physostigmine (Reference)                                                                      0.31      20%                                                ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsule or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweeting agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present inventions are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

Examples of the compounds of this invention include

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]formamide;

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)-4,4-dimethyl-cyclohexyl]formamide;

N-[1-(1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl)cyclohexyl]acetamide;

cis-N-[1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl)-4-(1,1-dimethylethyl)-cyclohexyl]acetamide;

N-[1-[1,6-Dihydro-6-oxo-1-(phenylmethyl)-3-pyridinyl]cyclohexyl]formamide;

5-(1-Aminocyclohexyl)-2(1H)-pyridinone;

5-(1-Amino-4,4-dimethylcyclohexyl)-2(1H)-pyridinone;

5-(1-Aminocyclohexyl)-1-methyl-2(1H)-pyridinone;

5-(1-Aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone;

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]benzamide;

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]acetamide;

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]propionamide;

N-1-[1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl]cyclohexyl]benzeneacetamide;

N-[1-[1,6-Dihydro-6-oxo-1-(phenylmethyl)-3-pyridinyl]cyclohexyl]benzeneacetamide;

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]chloroacetamide;

N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl][4-(4-fluorobenzoyl)]-1-piperidineacetamide;

5-[1-(Methylamino)cyclohexyl]-1-methyl-2(1H)-pyridinone;

5-[1-(Methylamino)cyclohexyl]-1-(phenylmethyl)-2(1H)-pyridinone;

N-[1-[1,6-Dihydro-6-oxo-1-(2-propynyl)-3-pyridinyl]cyclohexyl]formamide;

5-(1-Aminocyclohexyl)-1-[4-(pyrrolidin-1-yl)-2-butynyl]-2(1H)-pyridinone;

N-[1-[6-(Benzoyloxy)-3-pyridinyl]cyclohexyl]benzamide;

5-(1-Hydroxycyclohexyl)-2(1H)-pyridinone;

5-(4,4-dimethyl-1-hydroxycyclohexyl)-2(1H)-pyridinone;

5-(1-Hydroxycyclohexyl)-1-methyl-2(1H)-pyridinone;

5-[4-(1,1-Dimethylethyl)-1-hydroxycyclohexyl]-1-methyl-2(1H)-pyridinone;

5-(1-Hydroxycyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone;

5-(1-Hydroxycyclohexyl)-2-methoxypyridine;

5-[4-(1,1-Dimethylethyl)-1-hydroxycyclohexyl]-2-methoxypyridine;

The following examples are presented in order to illustrate thisinvention.

EXAMPLE 1 5-Bromo-2-(triisopropylsilyloxy)pyridine

Triisopropylsilyl trifluoromethanesulfonate (65.4 g) was added dropwiseto a solution of 5-bromo-2(1H)-pyridinone (33.8 g) and 2,6-lutidine(31.1 g) in 775 ml of dichloromethane at 0° C. The resulting solutionwas stirred for 15 minutes, and then it was poured into water and thelayers were separated. The aqueous phase was extracted withdichloromethane, and the combined organic layers were dried overmagnesium sulfate and concentrated to give a liquid. The product wasslurried with silica gel and hexanes. Filtration gave 64.6 g of oil.

EXAMPLE 2 5-(1-Hydroxycyclohexyl)-2(1H)-pyridinone

A solution of n-butyllithium (2.5M in hexanes, 92 ml) was added dropwiseover 50 minutes to a solution of 5-bromo-2-triisopropylsilyloxypyridine(69.0 g) in 800 ml of diethyl ether at -40° to -45° C. The resultingsolution was stirred at -40° to -45° C. for 0.5 hour, and thencyclohexanone (22.5 g) in 25 ml of diethyl ether was added dropwise. Themixture was allowed to warm to 0° C., quenched with saturated ammoniumchloride solution, and extracted with diethyl ether. The combinedorganic phases were washed with saturated sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to give 79 g ofcrude product as an oil.

The product formed above was dissolved in 260 ml of acetonitrile at 0°C., and hydrofluoric acid (48% in water, 7.1 ml) was added rapidly,dropwise. The thick suspension was stirred for 5 minutes, and then theprecipitated product was collected by filtration, yielding 29.0 g of5-(1-hydroxycyclohexyl)-2(1H)-pyridinone as a powder. An analyticalsample was obtained by recrystallization from methanol/diethyl ether,m.p. 194°-196° C.

ANALYSIS: Calculated for C₁₁ H₁₅ NO₂ : 68.37%C; 7.82%H; 7.25%N. Found:68.46%C; 7.72%H; 7.23%N.

EXAMPLE 3 5-(4,4-Dimethyl-1-hydroxycyclohexyl-2(1H)-pyridinone

A solution of n-butyllithium (1.6M in hexanes, 132 ml) was addeddropwise over 50 minutes to a solution of5-bromo-2-triisopropylsilyloxypyridine (63.6 g) in 750 ml of diethylether at -45° to -40° C. The resulting solution was stirred at -45° to-40° C. for 0.5 hour, and then 4,4-dimethylcyclohexanone (26.5 g) in 50ml of diethyl ether was added dropwise. The mixture was allowed to warmto 0° C., quenched with saturated ammonium chloride solution, andextracted with diethyl ether. The combined organic phases were washedwith saturated sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated to give 75 g of crude product as an oil.

The product formed above was dissolved in 260 ml of acetonitrile at 0°C., and hydrofluoric acid (48% in water, 7.1 ml) was added rapidlydropwise. The thick suspension was stirred for 5 minutes, and then theprecipitated product was collected by filtration, yielding 26.0 of5-(4,4-dimethyl-1-hydroxycyclohexyl)-2(1H)-pyridinone as a powder. Ananalytical sample was obtained by two recrystallizations from methanol,m.p. 210°-211° C.

ANALYSIS: Calculated for C₁₃ H₁₉ NO: 70.56%C; 8.65%H; 6.33%N. Found:70.67%C; 8.70%H; 6.35%N.

EXAMPLE 4 5-(1-Hydroxycyclohexyl)-2-methoxypyridine

A solution of n-butyllithium (1.6M in hexanes, 150 ml) was addeddropwise over 1 hour to a mechanically stirred solution of5-bromo-2-methoxypyridine (39.3 g) in 800 ml of diethyl ether at -40° C.The resulting slurry was stirred at -40° C. to -45° C. for 45 minutes,and then cyclohexanone (23.5 g) in 50 ml of diethyl ether was addeddropwise over 1 hour. The mixture was allowed to warm to 0° C. overabout 1 hour, and then the reaction was quenched with saturated ammoniumchloride solution. The layers were separated, and the aqueous phase wasextracted with diethyl ether. The combined organic phases were washedwith saturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to yield a semi-solid material. Triturationwith pentane provided 29.0 g of product as a powder. Recrystallizationof 8 g of the product gave 6.2 g of plates, m.p. 74°-75° C.

ANALYSIS: Calculated for C₁₂ H₁₇ NO₂ : 69.54%C; 8.27%H; 6.76%N. Found:69.53%C; 8.37%H; 6.76%N.

EXAMPLE 5 cis/trans5-[4-(1,1-Dimethylethyl)-1-hydroxycyclohexyl]-2-methoxypyridine

A solution of n-butyllithium (1.6M in hexanes, 100 ml) was addeddropwise over 1 hour to a mechanically stirred solution of5-bromo-2-methoxypyridine (40 g) in 800 ml of diethyl ether at -40° C.The resulting slurry was stirred at -40° C. to -45° C. for 45 minutes,and then 4-t-butyl cyclohexanone (39 g) in 240 ml of diethyl ether wasadded dropwise over 1.5 hours. The mixture was allowed to warm to 0° C.over 1 hour, and then the reaction was quenched with saturated ammoniumchloride solution. The layers were separated, and the aqueous phase wasextracted with diethyl ether. The combined organic phases were washedwith saturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to yield a semi-solid material. Triturationwith pentane provided 29 g of powder as a mixture of epimers which wasused in subsequent reactions without further purification.

EXAMPLE 6 5-(1-Hydroxycyclohexyl)-1-methyl-2(1H)-pyridinone

A mixture of 5-(1-hydroxycyclohexyl)-2-methoxypyridine (17.1 g), methyliodide (11.7 g) and potassium carbonate (22.8 g) was heated in 330 mL ofrefluxing acetonitrile for 18 hours. The mixture was cooled andfiltered, and the solids were washed with methanol. The filtrate wasconcentrated to yield 14.0 g of powder, which was used in subsequentreactions without further purification.

EXAMPLE 7cis/trans-5-[4-(1,1-Dimethylethyl)-1-hydroxycyclohexyl]-1-methyl-2(1H)-pyridinone

A mixture of cis/trans5-[4-(1,1-dimethylethyl)-1-hydroxycyclohexyl]-2-methoxypyrridine (29.0g), methyl iodide (15.6 g), and potassium carbonate (30.0 g) was heatedin 440 mL of refluxing acetonitrile for 18 hours. The resultingsuspension was cooled and filtered, and the solids were washed withmethanol. The filtrate was concentrated to a small volume, and theprecipitated product was collected to afford 32 g of powder, which wasused in subsequent reactions without purification.

EXAMPLE 8 5-(1-Hydroxycyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone

A mixture of 5-(1-hydroxycyclohexyl)-2-methoxy pyridine (26.3 g), benzylbromide (21.7 g) and potassium carbonate (35 g) was heated in 500 mL ofrefluxing acetonitrile for 17 hours. The mixture was cooled andfiltered, and the solids were washed with methanol. The filtrate wasconcentrated to give 39.5 g of an oil. HPLC on silica gel (elution withethyl acetate) afforded 20.8 g of solid.

EXAMPLE 9 N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl] formamidehydrochloride

Concentrated sulfuric acid (150 ml) was added dropwise over 45 minutesto a suspension of 5-(1-hydroxycyclohexyl)-2(1H)-pyridinone (37.0 g) andpotassium cyanide (370 g) in 770 ml of trifluoroacetic acid at 0° C. Theresulting suspension was stirred at room temperature for 17 hours andthen cooled to 0° C., and diethyl ether was added slowly. The solventwas decanted, and the solids were washed with diethyl ether. The productwas then dissolved in methanol and neutralized withpoly-4-vinylpyridine. The polymer was removed by filtration, and thefiltrate was concentrated to yield a white foam, which was dissolved inmethanol and acidified with ethereal HCl. The solvent was removed invacuo to afford a foam (43.2 g) which was used in subsequent reactionswithout further purification.

EXAMPLE 10 N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)-4,4-dimethylcyclohexyl]formamide hydrochloride

Concentrated sulfuric acid (54 ml) was added dropwise over 45 minutes toa suspension of 5-(4,4-dimethyl-1-hydroxycyclohexyl)-2(1H)-pyridinone(15 g) and potassium cyanide (13.2 g) in 272 ml of trifluoroacetic acidat 0° C. The resulting suspension was stirred at room temperature for 17hours and then cooled to 0° C., and diethyl ether was added slowly. Thesolvent was decanted, and the solids were washed with diethyl ether. Theproduct was then dissolved in methanol and neutralized withpoly-4-vinylpyridine. The polymer was removed by filtration, and thefiltrate concentrated, yielding a foam, which was dissolved in methanoland acidified with ethereal HCl. The volume of solvent was reduced invacuo, and the precipitated solid (7.1 g) was collected and used insubsequent reactions without further purification.

EXAMPLE 11N-[1-(1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl)cyclohexyl]-acetamide

Concentrated sulfuric acid (40 ml) was added dropwise over 45 minutes toa suspension of 5-(1-hydroxycyclohexyl)-1-methyl-2(1H)-pyridinone (6.38g) in 120 ml of acetonitrile at 0° C. The resulting solution was stirredat room temperature for 16 hours and then poured over ice, and the pHwas adjusted to 8. The product was extracted into dichloromethane, andthe combined organic layers were washed with brine, dried over magnesiumsulfate, filtered and concentrated to afford a foam. Trituration withethyl acetate afforded 6.3 g of powder. Recrystallization fromisopropanol/diisopropyl ether gave 4.86 g ofN-[1-(1,6-dihydro-1-methyl-6-oxo-3-pyridinyl)cyclohexyl]-acetamide ascrystals, m.p. 194°-195° C.

ANALYSIS: Calculated for C₁₄ H₂₀ N₂ O₂ : 67.72%C; 8.12%H; 11.28%N.Found: 67.74%C; 8.12%H; 11.28%N.

EXAMPLE 12cis-N-[1-(1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl)-4-(1,1-dimethylethyl)cyclohexyl]acetamide

Concentrated sulfuric acid (28 ml) was added dropwise over 45 minutes tostirred suspension of5-[1-hydroxy-4-(1,1-dimethylethyl)cyclohexyl]-1-methyl-2(1H)-pyridinone(5.5 g) in 83 ml of acetonitrile at 0° C. The resulting solution wasstirred at room temperature for 16 hours, and then it was poured overice, and the pH was adjusted to 8. The product was extracted intodichloromethane, and the combined organic layers were washed withsaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to leave 3.45 g of powder. Recrystallizationfrom isopropanol/diisopropyl ether afforded 2.2 g of powder, m.p.231°-232° C.

ANALYSIS: Calculated for C₁₈ H₂₈ N₂ O₂ : 71.02%C; 9.27%H; 9.20%N. Found:70.68%C; 9.10%H; 9.13%N.

EXAMPLE 13N-[1-[1,6-Dihydro-6-oxo-1-(phenylmethyl)-3-pyridinyl]-cyclohexyl]formamidehydrochloride

Concentrated sulfuric acid (60 ml) was added dropwise over 30 minutes toa suspension of 5-(1-hydroxycyclohexyl-1-(phenylmethyl)-2(1H)-pyridinone(20.3 g) and potassium cyanide (14 g) in 290 ml of trifluoroacetic acidat 0° C. The resulting suspension was stirred at room temperature for 18hours and then cooled to 0° C., and diethyl ether was added slowly. Thesolvent was decanted, and the solids were washed with diethyl ether. Theproduct was then dissolved in methanol and neutralized withpoly-4-vinylpyridine. The polymer was removed by filtration, and thefiltrate concentrated to yield a foam. The product was converted to itsHCl salt and used in subsequent reactions without further purification.

EXAMPLE 14 5-(1-Aminocyclohexyl)-2(1H)-pyridinone hydrochloride

A solution of N-[1-(1,6-dihydro-6-oxo-3-pyridinyl)cyclohexyl]formamidehydrochloride (43.0 g) in 700 ml of methanol was heated at reflux for 17hours, and then cooled and concentrated. The residual oil was trituratedwith methanol affording 13.1 g of a white powder. Recrystallization frommethanol gave 5.5 g of crystals, m.p. 233°-234° C.

ANALYSIS: Calculated for C₁₁ H₁₇ ClN₂ O: 57.77%C; 7.49%H; 12.25%N.Found: 57.89%C; 7.43%H; 12.26%N.

EXAMPLE 15 5-(1-Amino-4,4-dimethylcyclohexyl)-2(1H)-pyridinonehydrochloride

A solution ofN-[1-(1,6-dihydro-6-oxo-3-pyridinyl)-4,4-dimethylcyclohexyl]formamidehydrochloride (7.05 g) in 125 ml of methanol was heated at reflux for 24hours, and then the solution was cooled and concentrated in vacuo to avolume of 25 ml. The precipitated powder was collected, affording 3.07 gof analytically pure 5-(1-amino-4,4-dimethylcyclohexyl)-2(1H)-pyridinonehydrochloride, m.p. 229°-230° C.

ANALYSIS: Calculated for C₁₃ H₂₀ N₂ O.HCl: 60.81%C; 8.24%H; 10.91%N.Found: 60.42%C; 8.17%H; 10.83%N.

EXAMPLE 16 5-(1-Aminocyclohexyl)-1-methyl-2(1H)-pyridinone hydrochloride

Concentrated sulfuric acid (67 ml) was added dropwise over 45 minutes toa suspension of 5-(1-hydroxycyclohexyl)-1-methyl-2(1H)-pyridinone (17.2g) and potassium cyanide (16.3 g) in 334 ml of trifluoroacetic acid at0° C. The resulting suspension was stirred at room temperature for 18hours, and then it was cooled to 0° C., and diethyl ether was addedslowly. The solvent was decanted, and the solids were washed withdiethyl ether. The product was then dissolved in methanol andneutralized with poly-4-vinylpyridine. The polymer was removed byfiltration, and the filtrate concentrated to yield a foam. The foam wasdissolved in methanol, acidified with ethereal hydrochloric acid andconcentrated, affording 17.1 g of foam.

The product formed above was dissolved in 300 ml of methanol and heatedat reflux for 16 hours. The resulting solution was cooled andconcentrated in vacuo to a volume of 50 ml. The precipitated product wascollect, affording 10.9 g of analytically pure product as a powder, m.p.240°-245° C.

ANALYSIS: Calculated for C₁₂ H₁₉ ClN₂ O: 59.38%C; 7.89%H; 11.54%N.Found: 59.12%C; 7.83%H; 11.51%N.

EXAMPLE 17 5-(1-Aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinonehydrochloride

A solution ofN-[1-[1,6-dihydro-6-oxo-1-(phenylmethyl)-3-pyridinyl]-cyclohexyl]formamidehydrochloride (13.4 g) in 200 ml of methanol was heated at reflux for 17hours. The mixture was cooled, and the resultant crystals werecollected, affording 5.6 g of analytically pure5-(1-aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone hydrochloride,m.p. 248°-250° C. (dec).

ANALYSIS: Calculated for C₁₈ H₂₃ ClN₂ O: 67.81%C; 7.27%H; 8.79%N. Found:67.76%C; 7.20%H; 8.75%N.

EXAMPLE 18 N-[1-[6-(Benzoyloxy)-3-pyridinyl]cyclohexyl]benzamide

A solution of benzoic anhydride (13.9 g), triethylamine (11.6 g),4-(N,N-dimethylamino)pyridine (0.17 g) and5-(1-aminocyclohexyl)-2(1H)-pyridinone hydrochloride (6.15 g) in 100 mlof dichloromethane was stirred at room temperature for 4 hours. Theresulting solution was diluted with dichloromethane, washed with waterand brine, dried over magnesium sulfate, filtered, and concentrated togive 11.5 g of solid. Recrystallization from ethyl acetate/hexanesafford 5.6 g of product as needles, m.p. 167°-168.5° C.

ANALYSIS: Calculated for C₂₅ H₂₄ N₂ O₃ : 74.98%C; 6.04%H; 6.99%N. Found:74.80%C; 6.08%H; 6.99%N.

EXAMPLE 19 N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]benzamide

A solution of N-[1-[6-(benzoyloxy)-3-pyridinyl]cyclohexyl]benzamidehydrochloride (10.4 g) was heated in 75 ml of refluxing methanol for 1hour. The solution was cooled, and the solvent was removed in vacuo. Theresidual oil was triturated with a mixture of ethyl acetate and hexanes,affording 5.9 g of crude product as a solid. Recrystallization fromisopropyl alcohol gave 1.91 g of a flocculent solid, m.p. 223°-224° C.

ANALYSIS: Calculated for C₁₈ H₂₀ N₂ O₂ : 72.95%C; 6.80%H; 9.45%N. Found:72.85%C; 6.60%H; 9.73%N.

EXAMPLE 20 N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]acetamide

Sodium methoxide solution (25% in methanol, 6 ml) was added to asuspension of 5-(1-aminocyclohexyl)-2(1H)-pyridinone hydrochloride (6.0g) in 100 ml of methanol, and the mixture was stirred at roomtemperature for 10 minutes. The solvent was removed in vacuo, and theresidual solids were suspended in 260 ml of dichloromethane.Poly-4-vinylpyridine (5.42 g), acetic anhydride (2.67 g) and a catalyticamount of 4-(N,N-dimethylamino)pyridine were added, and the mixture wasstirred at room temperature for 2 hours. The suspension was filtered andthe solid residue was washed with methanol. The filtrate wasconcentrated, leaving 4.9 g of solid. Recrystallization from methanolgave 1.69 g of product (m.p. 238°-242° C. dec) in two crops, each ofwhich was analytically pure.

ANALYSIS: Calculated for C₁₃ H₁₈ N₂ O: 66.64%C; 7.74%H; 11.96%N. Found:66.47%C; 7.69%H; 11.87%N.

EXAMPLE 21 N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]propionamide

A solution of propionic anhydride (8.89 g), triethylamine (13.8 g),4-(N,N-dimethylamino)pyridine (47 mg) and5-(1-aminocyclohexyl)-2(1H)-pyridinone hydrochloride (7.81 g) in 170 mlof dichloromethane was stirred at room temperature for 4 hours. Theresulting mixture was diluted with water and extracted withdichloromethane. The combined organic layers were washed with saturatedsodium bicarbonate solution and brine, dried over magnesium sulfate,filtered and concentrated to give 6.1 g of a solid. Recrystallizationfrom ethanol gave 4.6 g of product as crystals, m.p. 227°-228° C.

ANALYSIS Calculated for C₁₄ N₂₀ N₂ O₂ : 67.72%C; 8.12%H; 11.28%N. Found:67.42%C; 8.18%H; 11.18%N.

EXAMPLE 22N-1-[1,6-Dihydro-1-methyl-6-oxo-3-pyridinyl]cyclohexyl]-benzeneacetamide

Phenylacetic acid (4.2 g) was added to a solution of carbonyldiimidazole (5.1 g) in 280 mL of dichloromethane at room temperature.The resulting solution was stirred for 1 hour, and then triethylamine(3.2 g) and 5-(1-aminocyclohexyl)-1-methyl-2(1H)-pyridinonehydrochloride (6.9 g) were added sequentially. The resulting suspensionwas stirred at room temperature for 16 hours, and then water was added,and the layers were separated. The aqueous phase was extracted withethyl acetate, and the combined organic layers were washed withsaturated sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated to afford 6.1 g of solid. The product wasrecrystallized twice from isopropanol to give 1.68 g of product ascrystals, m.p. 221°-223° C.

ANALYSIS: Calculated for C₂₀ H₂₄ N₂ O₂ : 74.05%C; 7.46%H; 8.63%N. Found:73.69%C; 7.64%H; 8.49%N.

EXAMPLE 23 N-[1-[1,6-Dihydro-6-oxo-1-(phenylmethyl)-3-pyridinyl]-cyclohexyl]-benzeneacetamide

Phenylacetyl chloride (1.6 g) was added to a well stirred suspension of5-(1-aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone (2.9 g),poly-4-vinylpyridine (2.1 g) and a catalytic amount of4-(N,N-dimethylamino)pyridine in 70 ml of dichloromethane, and theresulting mixture was stirred at room temperature for 3 hours. Thereaction mixture was filtered and the filtrate concentrated to give 4.1g of oil. Column chromatography (silica gel, elution with ethyl acetate)afforded 2.1 g of foam. Recrystallization from ethyl acetate/hexanesgave 1.7 g of analytically pure product as needles, m.p. 152°-153° C.

ANALYSIS: Calculated for C₂₆ H₂₈ N₂ O₂ : 77.97%C; 7.05%H; 6.99%N. Found:77.97%C; 7.07%H; 6.96%N.

EXAMPLE 24N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]chloroacetamide

Triisopropylsilyl trifluoromethane sulfonate (9.98 g) was added dropwiseto a suspension of 5-(1-aminocyclohexyl)-2-(1H)-pyridinone (6.26 g) and2,6-lutidine (3.49 g) in 330 mL of dichloromethane. The resultingmixture was stirred at room temperature for 2 hours and then poured intowater. The layers were separated, and the aqueous phase was extractedwith dichloromethane. The combined organic layers were washed with waterand brine, dried over MgSO₄ and concentrated to give 9.66 g of oil.

A portion of the product formed above (7.83 g) was combined with 4.5 gof poly-4-vinylpyridine, chloroacetic anhydride (3.8 g) and a catalyticamount of 4-(N,N-dimethylamino)pyridine in 100 mL of dichloromethane.The mixture was stirred for 2 hours and then filtered. The filtrate wasconcentrated, affording 1.9 g of product as a solid.

EXAMPLE 25N-[1-(1,6-Dihydro-6-oxo-3-pyridinyl)cyclohexyl]-[4-(4-fluorobenzoyl)]-1-piperidineacetamide

A mixture ofN-[1-(1,6-dihydro-6-oxo-3-pyridinyl)cyclohexyl]chloroacetamide (1.74 g),4-(4-fluorobenzoyl)piperidine hydrochloride (1.57 g) anddiisopropylethylamine (1.67 g) was heated in 35 ml of refluxingacetonitrile for 1 hour. The resulting suspension was cooled to roomtemperature and the solid was collected, yielding 1.8 g of solid.Recrystallization from methanol gave 1.1 g of product as a solid, m.p.243°-245° C. (dec).

ANALYSIS: Calculated for C₂₅ H₃₀ FN₃ O₃ : 68.32%C; 6.88%H; 9.56%N.Found: 68.23%C; 7.07%H; 9.57%N.

EXAMPLE 26 5-[1-(Methylamino)cyclohexyl]-1-methyl-2(1H)-pyridinonedihydrochloride

A solution of acetic acid (25.0 g) in 70 ml of tetrahydrofuran was addeddropwise over 1 hour to a mechanically stirred suspension of sodiumborohydride (1.58 g) andN-[1-[1,6-dihydro-1-methyl-6-oxo-3-pyridinyl]cyclohexyl]-formamide (20.0g) in 420 ml of tetrahydrofuran at 0° C. The resulting mixture washeated to reflux and stirred at that temperature for 17 hours. Thereaction mixture was cooled to room temperature, and the solvent wasremoved in vacuo. The residue was quenched with water, and the productwas extracted into dichloromethane. The combined organic layers weredried over magnesium sulfate, filtered, and concentrated to provide 12.7g of oil. Purification by column chromatography on silica gel (elutionwith triethylamine/methanol/ethyl acetate) afforded 6.5 g of product asan oil, which was dissolved in methanol and acidified with ethereal HCl.The solvent was removed in vacuo, and the product crystallized fromethanol/ethyl acetate. Two recrystallizations from ethanol provided 3.3g of an analytically pure solid, m.p. 190°-191.5° C.

ANALYSIS: Calculated for: 53.25%C; 7.56%H; 9.55%N. Found: 53.22%C;7.70%H; 9.50%N.

EXAMPLE 275-[1-(Methylamino)cyclohexyl]-1-(phenylmethyl)-2(1H)-pyridinone fumarate

A solution of acetic acid (19.86 g) in 50 ml of tetrahydrofuran wasadded dropwise over 1 hour to a mechanically stirred suspension ofsodium borohydride (12.3 g) andN-[1-[1,6-dihydro-1-(phenylmethyl)-6-oxo-3-pyridinyl]-cyclohexyl]formamide(20.4 g) in 328 ml of tetrahydrofuran at 0° C. The resulting mixture washeated to reflux and stirred at that temperature for 17 hours. Thereaction mixture was cooled to room temperature, and the solvent wasremoved in vacuo. The residue was quenched with water, and the productwas extracted into dichloromethane. The combined organic layers weredried over magnesium sulfate, filtered, and concentrated to provide 14.5g of oil. Purification by HPLC on silica gel (elution withtriethylamine/methanol/ethyl acetate) afforded 7.5 g of product as anoil. A portion of the product (4.3 g) was dissolved in hot ethylacetate, and an equivalent amount of fumaric acid in hot methanol wasadded to the solution. The solution was allowed to cool, and theresultant crystals were collected to afford 5.2 g of analytically purematerial, m.p. 184°-185° C.

ANALYSIS: Calculated for: 66.97%C; 6.84%H; 6.79%N. Found: 66.91%C;6.86%H; 6.77%N.

EXAMPLE 28N-[1-[1,6-Dihydro-6-oxo-1-(2-propynyl)-3-pyridinyl]-cyclohexyl]formamide

A well stirred mixture ofN-[1-(1,6-dihydro-6-oxo-3-pyridinyl)-cyclohexyl]formamide (13.8 g),3-bromo-1-trimethylsilyl-1-propyne (8.87 g) and potassium carbonate(17.3 g) in 250 mL of dimethylformamide was kept at room temperature for18 hours. The mixture was filtered, and the solvent was removed invacuo, leaving 16.2 g of solid.

A portion of the compound prepared above (12.1 g) was dissolved in 150mL of tetrahydrofuran at 0° C. and treated dropwise withtetra-n-butylammonium fluoride (1M in tetrahydrofuran, 36.1 mL). Theresulting solution was stirred for 0.5 hour and then poured into water.The aqueous phase was separated and extracted with ethyl acetate. Thecombined organic layers were dried over MgSO₄ and concentrated to give6.8 g of crude product. This was combined with an additional 3.3 gobtained as above, and purified via HPLC on silica gel (elution withmethanol/ethyl acetate) to give 7.2 g of pure compound.

EXAMPLE 295-(1-Aminocyclohexyl)-1-[4-(pyrrolidin-1-yl)-2-butynyl]-2(1H)-pyridinone

Copper (I) chloride (0.9 g) was added in one portion to a mixture ofN-[1-[1,6-dihydro-6-oxo-1-(2-propynyl)-3-pyridinyl]-cyclohexyl]formamide(6.7 g), paraformaldehyde (0.94 g) and pyrrolidine (2.2 g) in 26 mL ofdioxane. The resulting solution was stirred at room temperature for 2hours, and then it was acidified with 10% HCl solution. The aqueouslayer was separated, extracted with dichloromethane, and basified withNa₂ CO₃ (s). The product was extracted into dichloromethane, and thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated to afford an oil. The crude product was deposited on silicagel (35 g) and filtered through a pad of silica gel (elution with 20%methanol/80% ethyl acetate). Concentration of the filtrate afforded 6.02g of product. A portion of the product (5.42 g) was dissolved inmethanol and acidified with etheral HCl. The resulting foam was used inthe subsequent reaction without further purification.

The hydrochloride (15.9 mmol) formed above was dissolved in 90 mL ofmethanol, and the resulting solution was heated at reflux for 16 hours.The solution was cooled, and the solvent was removed in vacuo. Theresidue was basified with saturated NaHCO₃ solution, and the product wasextracted into dichloromethane. The combined organic layers were driedover K₂ CO₃, filtered, and concentrated to give 4.3 g of crude product,which was filtered through silica gel (elution with ethyl acetate) toprovide 4.0 g of product as a solid. Recrystallization from ethylacetate/hexanes gave 1.9 g of analytically pure product, m.p. 97°-99° C.

ANALYSIS: Calculated for C₁₉ H₂₇ N₃ O: 72.81%C; 8.68%H; 13.41%N. Found:72.69%C; 8.59%H; 13.28%N.

We claim:
 1. A compound having the formula, ##STR42## where n is 1, 2 or3;R₃ is hydrogen or loweralkyl; and R₄ is hydrogen or loweralkyl.
 2. Thecompound as defined in claim 1, where R₃ and R₄ are both hydrogen. 3.The compound as defined in claim 1, where n is
 2. 4. The compound asdefined in claim 1, which is 5-(1-hydroxycyclohexyl)-2-methoxypyridine.5. The compound as defined in claim 1, which is5-[4-(1,1-dimethylethyl)-1-hydroxycyclohexyl]-2-methoxypyridine.